Seeinstructions): The design of an effective AIDS vaccine is complicated by the fact that virtually every HIV/SIV-specific adaptive immune response aimed at preventing and/or controlling the infection will inevitably result in the generation of activated HIV/SIV-specific CD4+ T cells that may paradoxically facilitate virus transmission or disease progression after infection. We here hypothesize that the best correlate of protective efficacy from pathogenic SIV challenge for a candidate AIDS vaccine is the induction of robust and persistent SIV-specific mucosal CD8+ T cell responses in the presence of low levels of mucosal activated CD4+CCR5+ T cells. The overall aim of this project is to test this hypothesis by assessing the ability of various immunogens to induce SIV-specific CD8+ T cell responses as well as activated CD4+CCR5+ T cells. In Aim #1, the magnitude, phenotype, and duration of these SIV-specific T cell responses will be evaluated in conjunction with an assessment of the level of activated/proliferating CD4+ T cells induced by these vaccine regimens. In Aim #2, we will assess the turnover of the vaccine-induced systemic and mucosal CD8+ and CD4+ T cells using BrdU labeling. In Aim #3, we will use the two best immunization regimens (as defined by Aim #1) in an SIV challenge experiment to directly assess the relationship between these vaccine-induced CD8+ and CD4+ T cell responses and protection against SIV disease progression. In Aim #4, we will determine if the "protective" profile of high mucosal CD8+ T cell responses in the presence of low CD4+ T cell activation is augmented by antibody-mediated CD4+ T cell depletion performed after the last booster immunization. We expect that these studies will advance our understanding of the correlates of immune protection at the level of mucosal tissues and thus help determine which AIDS vaccine regimen is more likely to be effective in human clinical studies. RELEVANCE (Seeinstructions): Given the magnitude of the AIDS pandemic, an effective vaccine is desperately needed to contain the damage caused by this virus. Unfortunately, the design and development of such a vaccine has been beyond the reach of the scientific community, partly because we do not know the immunological correlates of protection from HIV disease progression. This project is relevant to human health as its goal is to identify the correlates of safety, immunogenicity, and efficacy for a series candidate HIV vaccines.